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Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation.

ABSTRACT: Allogeneic blood or BM transplantation (BMT) is the most commonly applied form of adoptive cellular therapy for cancer. In this context, the ability of donor T cells to respond to recipient antigens is coopted to generate graft-versus-tumor (GVT) responses. The major reason for treatment failure is tumor recurrence, which is linked to the eventual loss of functional, host-specific CTLs. In this study, we have explored the role of recipient antigen expression by nonhematopoietic cells in the failure to sustain effective CTL immunity. Using clinically relevant models, we found that nonhematopoietic antigen severely disrupts the formation of donor CD8+ T cell memory at 2 distinct levels that operate in the early and late phases of the response. First, initial and direct encounters between donor CD8+ T cells and nonhematopoietic cells blocked the programming of memory precursors essential for establishing recall immunity. Second, surviving CD8+ T cells became functionally exhausted with heightened expression of the coinhibitory receptor programmed death-1 (PD-1). These 2 factors acted together to induce even more profound failure in long-term immunosurveillance. Crucially, the functions of exhausted CD8+ T cells could be partially restored by late in vivo blockade of the interaction between PD-1 and its ligand, PD-L1, without induction of graft-versus-host disease, suggestive of a potential clinical strategy to prevent or treat relapse following allogeneic BMT.

SUBMITTER: Flutter B

PROVIDER: S-EPMC2964967 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants.

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| S-EPMC9310529 | biostudies-literature

T cell-specific notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells.

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| S-EPMC3660433 | biostudies-literature

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CD8 T cell exhaustion in human visceral leishmaniasis.

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| S-EPMC3873784 | biostudies-literature

CD146 expression on primary nonhematopoietic bone marrow stem cells is correlated with in situ localization.

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Disturbed mitochondrial dynamics in CD8+ TIL reinforce epigenetic programming linked with T cell exhaustion

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-09-01 | GSE144584 | GEO

Disturbed mitochondrial dynamics in CD8+ TIL reinforce epigenetic programming linked with T cell exhaustion

Project description:The metabolic challenges present in tumors attenuate the metabolic fitness and anti-tumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulating depolarized mitochondria as a result of declined mitophagy activity display functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, declined mitochondrial fitness in TILs is induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signal. Forcing the accumulation of depolarized mitochondria with pharmacological interventions induces epigenetic reprogramming for terminal exhaustion, indicating that mitochondrial deregulation is indeed a cause – rather than a consequence – of T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhances T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal new insights on how mitochondrial dynamics and quality orchestrate T cell anti-tumor responses and commitment to the exhaustion program.

2020-09-01 | GSE144583 | GEO

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